This proposal explores the molecular events happening in vivo and in vitro as a result of the interactions between pemphigus and pemphigoid autoantibodies and the cell surface of epidermal cells. These studies will be performed first with IgG fractions obtained from patients with these disorders and later with monoclonal antibodies produced by human-human pemphigus-hybridomas. The in vitro studies will further define biochemically the cell surface antigens involved in these reactions, and the biological effects these antibodies have on epidermal cells in culture. Pemphigus antibodies are known to induce acantholysis in human skin explants and increase the rates of cell detachment from epidermal monolayers, independent of complement. Recent in vitro studies have shown that pemphigoid antibodies will bind the dermal epidermal junction of skin sections, activate complement from an added source, and subsequently release chemotactic factors for neutrophils, which in turn could split the epidermis from the dermis. In vivo studies carried out in our laboratory and described in this proposal have shown the following: a) that the intracorneal (stromal) injections of pemphigoid IgG induce a neutrophilic keratitis with splitting of the corneal epithelium from Bowman's membrane. Furthermore, the injected cornea shows pemphigoid antibodies bound to the epithelial-stromal junction. The clinical, histological and immunological findings induced by the pemphigoid IgG demonstrates for the first time the pathogenicity of these antibodies in vivo, duplicating the cutaneous findings of Bullous Pemphigoid; b) that passive transfer of pemphigus antibodies into hairless mice shows encouraging results. In one of the transfused animals an erosive dermatoses developed associated with circulating and in vivo skin-bound pemphigus antibodies. We postulate that an epidermal cell surface crosslinking phenomenon is produced by bound pemphigus antibodies, which may be responsible for the cellular detachment observed in vivo and in vitro. Activation of proteases, or impairment in function of certain "attachment" molecules (pemphigus antigen) may lead to cellular detachment. It is possible that during internalization of the "pemphigus antibody-cell surface antigen complex" there is an associated "regurgitation" of hydrolytic enzymes from the intracellular vacuolar system which may further perpetuate the detachment process.